Non-degradable, low swelling, water soluble radiopaque hydrogel polymer

ABSTRACT

Hydrogel compositions prepared from amine components and glycidyl ether components are provided which are biocompatible and suitable for use in vivo due, in part, to their excellent stability.

CROSS-REFERENCES TO RELATED APPLICATIONS

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STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

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REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

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BACKGROUND OF THE INVENTION

The present invention relates to the development of hydrogel polymercompositions that are non-degradable, low-swelling and initially watersoluble. More specifically, the hydrogel polymer compositions may beformed in situ and are useful as, e.g., embolic materials, bulkingagents, and inflation or support media for certain types of medicaldevices. The present invention additionally includes a kit for preparingthe hydrogel polymer compositions.

Hydrogel polymers are cross-linked hydrophilic macromolecules which haveuse in medical applications. While much progress has been made in suchapplications, further developments are needed to optimize the physicaland mechanical properties of these materials for particular in vivoapplications as described below.

One exemplary application for the hydrogel polymer materials discussedherein is as an inflation or support media for inflatable intraluminalgrafts or stent grafts. Examples of such inflatable stent grafts aredescribed in commonly owned U.S. Pat. No. 6,395,019 to Chobotov, pendingU.S. patent application Ser. No. 10/384,103 to Kari et al. entitled“Kink-Resistant Endovascular Graft”, filed Mar. 6, 2003, and U.S. patentapplication Ser. No. 10/327,711 to Chobotov et al., entitled “AdvancedEndovascular Graft”, filed Dec. 20, 2002, the entirety of each of whichis incorporated herein by reference. These documents describe a stentgraft in which additional structural integrity to the device may beachieved by the introduction of a polymeric fill material to channelsand cuffs located on the graft portion so to act as a graft inflationand support medium.

Ideally, the inflation or support medium used in the stent graftsdescribed above is biocompatible, has a cure time from about a fewminutes to tens of minutes, exhibits minimal volumetric shrinking andswelling as it cures, exhibits long-term stability (preferably for atleast ten years in vivo), poses as little an embolic risk as possible inthe pre-cure state, and exhibits adequate mechanical properties, both inits pre-and post- cure states. For instance, such a material should havea relatively low viscosity before solidification or curing to facilitatethe fill process into the stent graft.

Another application for the hydrogel polymers described herein is as amaterial for embolizing a body lumen such as a blood vessel or organ.Embolization, or the artificial blocking of fluid flow such as blood,may be used to treat a variety of maladies, including, by way of exampleonly, controlling bleeding caused by trauma, preventing profuse bloodloss during an operation requiring dissection of blood vessels,obliterating a portion of a whole organ having a tumor, blocking theblood flow into abnormal blood vessel structures such as aneurysms,arterio-venous malformations, arteriovenous fistulae, and blocking thepassage of fluids or other materials through various body lumens. Forsuch treatments, a variety of embolization technologies have beenproposed, including for example mechanical means (including particulatetechnology), and liquid and semi-liquid technologies. The particularcharacteristics of such technologies (such as, e.g., the size ofparticles, radiopacity, viscosity, mechanism of occlusion, biologicalbehavior and possible recanalization versus permanent occlusion, themeans by which the material is delivered to the target body site, etc.),are factors used by the physician in determining the most suitabletherapy for the indication to be treated.

Of the mechanical and particulate embolization technologies, the mostprevalent include detachable balloons, macro- and microcoils, gelfoamand polyvinyl alcohol sponges (such as IVALON, manufactured and sold byIvalon, Inc. of San Diego, Calif.), and microspheres. For example, oneembolization technique uses platinum and stainless steel microcoils.However, significant expertise is required to choose a proper coil sizefor the malady prior to delivery. Moreover, many anatomical sites arenot suitable for microcoils, and removal of microcoils has proved incertain circumstances difficult.

Liquid and semi-liquid embolic compositions include viscous occlusiongels, collagen suspensions, and cyanoacrylate (n-butyl and iso-butylcyanoacrylates). Of these, cyanoacrylates have an advantage over otherembolic compositions in their relative ease of delivery and in the factthat they are some of the only liquid embolic compositions currentlyavailable to physicians. However, the constituent cyanoacrylate polymershave the disadvantage of being biodegradable. Moreover, the degradationproduct, formaldehyde, is highly toxic to the neighboring tissues. SeeVinters et al. “The histotoxicity of cyanoacrylate: A selective review”,Neuroradiology, 1985; 27:279-291. Another disadvantage of cyanoacrylatematerials is that the polymer will adhere to body tissues and to the tipof the catheter. Thus, physicians must retract the catheter immediatelyafter injection of the cyanoacrylate embolic composition or riskadhesion of the cyanoacrylate and the catheter to tissue such as bloodvessels.

Another class of liquid embolic compositions is precipitative materials,which was invented in the late 1980's. See Sugawara et al.,“Experimental investigations concerning a new liquid embolizationmethod: Combined administration of ethanol-estrogen and polyvinylacetate”, Neuro. Med. Chir. (Tokyo) 1993; 33:71-76; Taki et al., “A newliquid material for embolization of arterio-venous malformations”, AJNR1990; 11:163-168; Mandai et al., “Direct thrombosis of aneurysms withcellulous acetate polymer: Part I: Results of thrombosis in experimentalaneurysms”, J. Neurosurgery 1992; 77:497-500. These materials employ adifferent mechanism in forming synthetic emboli than do thecyanoacrylate materials. Cyanoacrylate glues are monomeric and rapidlypolymerize upon contact with blood. On the other hand, precipitativematerials are pre-polymerized chains that precipitate into an aggregateupon contact with blood.

Ideally, embolic material formed in situ is biocompatible, has arelatively short cure time from about a few seconds to a few minutes,exhibits minimal to moderate controllable swelling upon curing, exhibitslong-term stability (preferably for at least ten years in vivo), andexhibits adequate mechanical properties, both in its pre- and post-curestate. For instance, such a material should have a relatively highviscosity before solidification or curing to facilitate safe andaccurate delivery to the target site.

The hydrogel polymer materials described herein are also suitable foruse in tissue bulking applications and more generally in inflatabledevices suitable for implantation in a mammalian body, which devices aretypically occlusive, such as those described variously in commonly ownedcopending U.S. patent application Ser. No. 10/461,853 to Stephens et al.entitled “Inflatable Implant”, filed Jun. 13, 2003, the entirety ofwhich is herein incorporated by reference. Such devices may be deliveredto a specific site in the body in a low profile form and expanded afterplacement to occlude or to support some region, vessel, or duct in thebody. Examples of tissue bulking applications include the treatment ofsphincter deficiencies exhibited by, e.g., gastroesophageal refluxdisease (GERD), urinary and fecal incontinence, augmentation of softtissue, and certain orthopedic indications. Many of the idealcharacteristics of embolic materials cited above are shared for theseapplications.

The majority of the hydrogel polymer materials in the literature containester, polyurethane or silicone groups. Even though such hydrogelpolymers are relatively easy to manufacture either by free radical,anionic, or cationic polymerizations, they tend to degrade in the body.For example, most hydrogels containing ester bonds can be hydrolyzedunder physiological pH.

Despite the advances made in the science of hydrogel polymercompositions for use in medical applications, there remains a need inthe art for hydrogel polymers having improved physical and mechanicalproperties for particular in vivo applications as described herein.

BRIEF SUMMARY OF THE INVENTION

The present invention is for an in situ formed hydrogel polymer,comprising: (a) a first amount of a diamine; and (b) a second amount ofa polyglycidyl ether; in which each of (a) and (b) are present in amammal or in a medical device located in a mammal in an amount toproduce an in situ formed hydrogel polymer that is biocompatible and hasa cure time after mixing of from about 10 seconds to about 30 minutes.The volume of the hydrogel polymer of the invention swells less than 30percent after curing and hydration.

The hydrogel composition may optionally comprise a radiopaque material.The radiopaque material is preferably selected from the group consistingof sodium iodide, potassium iodide, barium sulfate, Visipaque 320,Hypaque, Omnipaque 350 and Hexabrix.

In one embodiment, the hydrogel polymer comprises a polyglycidyl etherselected from the group consisting of trimethylolpropane triglycidylether, sorbitol polyglycidyl ether, polyglycerol polyglycidyl ether,pentaerythritol polyglycidyl ether, diglycerol polyglycidyl ether,glycerol polyglycidyl ether, trimethylolpropane polyglycidyl ether,polyethylene glycol diglycidyl ether, resorcinol diglycidyl ether,glycidyl ester ether of p-hydroxy benzoic acid, neopentyl glycoldiglycidyl ether, 1,6-hexanediol diglycidyl ether, bisphenol A (PO)2diglycidyl ether, hydroquinone diglycidyl ether, bisphenol S diglycidylether, terephthalic acid diglycidyl ester, and a mixture thereof.

In another embodiment, the hydrogel polymer comprises a diamine selectedfrom the group consisting of (poly)alkylene glycol having amino oralkylamino termini selected from the group consisting of polyethyleneglycol (400) diamine, di (3 aminopropyl) diethylene glycol r,polyoxypropylenediamine, polyetherdiamine, polyoxyethylenediamine,triethyleneglycol diamine, and a mixture thereof.

In yet another embodiment of the hydrogel polymer, the diamine componentis hydrophilic and the polyglycidyl ether component is hydrophilic priorto curing. Alternatively, in the hydrogel polymer, the diamine componentis hydrophilic and the polyglycidyl ether component is hydrophobic priorto curing. In another alternative, in the hydrogel polymer, the diaminecomponent is hydrophobic and the polyglycidyl ether component ishydrophilic prior to curing.

The hydrogel polymer composition of the invention can be formed in situin a mammal, or in a medical device located in the mammal, 1) in anintraluminal graft, 2) as an embolization device, 3) in an inflatableocclusion member, and 4) as a tissue bulking device. In one embodiment,the hydrogel polymer is form in situ in a mammal in an intraluminalgraft. When the hydrogel polymer is formed in an intraluminal graft, thehydrogel polymer is, in one embodiment, formed from: (a)di-(3-aminopropyl)diethylene glycol; and (b) a mixture of polyethyleneglycol glycidyl ether and trimethylolpropane triglycidyl ether.

The hydrogel polymer may also be formed in situ in a mammal or in amedical as an embolization device. When the hydrogel polymer is formedas an embolization device, the polymer is, in one embodiment, formedfrom: (a) a mixture of di-(3-aminopropyl)diethylene glycol andpolyoxyethylenediamine; and (b) sorbitol polyglycidyl ether. In anotherembodiment, the hydrogel polymer that is formed in situ in anembolization device is formed from: (a) di-(3-aminopropyl)diethyleneglycol; and (b) a mixture of pentaerythritol polyglycidyl ether andtrimethylolpropane polyglycidyl ether.

The hydrogel polymer may also be formed in situ in a mammal or in amedical device located in the mammal as an inflatable occlusion memberor as a tissue bulking device. In an inflatable occlusion member or as atissue bulking device, the hydrogel polymer is, in one embodiment,formed from: (a) di-(3-aminopropyl)diethylene glycol; and (b) sorbitolpolyglycidyl ether.

In yet another embodiment, the hydrogel polymer of the inventioncomprises a diamine component and a polyglycidyl component, in which thediamine component is present in an amount of between about 4 to about 20weight percent of said polymer; and the polyglycidyl ether is present inan amount of between about 15 to about 60 weight percent of saidpolymer.

In yet another embodiment, the hydrogel polymer of the inventioncomprises a diamine component and a polyglycidyl component, in which thediamine component is present in an amount of between about 5 to about 15weight percent of said polymer; and the polyglycidyl ether component ispresent in an amount of between about 25 to about 40 weight percent ofthe polymer.

In yet another embodiment, the hydrogel polymer of the inventioncomprises a diamine component and a polyglycidyl component, in which thediamine is di-(3-aminopropyl)diethylene glycol; the polyglycidyl etheris a mixture of polyethylene glycol glycidyl ether andtrimethylolpropane triglycidyl ether; and the radiopaque material isselected from the group consisting of sodium iodide, potassium iodide,barium sulfate, Visipaque 320, Hypaque, Omnipaque 350 and Hexabrix.

In yet another embodiment, the hydrogel polymer of the inventioncomprises a diamine component and a polyglycidyl component, in which thediamine is di-(3-aminopropyl)diethylene glycol; the polyglycidyl etheris selected from the group consisting of sorbitol polyglycidyl ether andpolyglycerol polyglycidyl ether; and the radiopaque material is selectedfrom the group consisting of sodium iodide, potassium iodide, bariumsulfate, Visipaque 320, Hypaque, Omnipaque 350 and Hexabrix.

In a certain embodiment of the hydrogel polymer, the diamine componentis present in an amount of between about 7 to about 60 weight percent ofthe polymer; and the polyglycidyl ether is present in an amount ofbetween about 7 to about 55 weight percent of the polymer.

In another embodiment of the hydrogel polymer, the diamine component ispresent in an amount of between about 10 to about 45 weight percent ofsaid polymer; and the polyglycidyl ether is present in an amount ofbetween about 14 to about 35 weight percent of said polymer.

In yet another embodiment of the hydrogel polymer, the diamine componentis present in an amount of between about 5 to about 30 weight percent ofsaid polymer; and the polyglycidyl ether is present in an amount ofbetween about 40 to about 90 weight percent of said polymer.

In yet another embodiment of the hydrogel polymer, the diamine componentis selected from the group consisting of di-(3-aminopropyl)diethyleneglycol and polyoxyethylenediamine; the polyglycidyl ether is sorbitolpolyglycidyl ether; and the radiopaque material is selected from thegroup consisting of sodium iodide, potassium iodide, barium sulfate,Visipaque 320, Hypaque, Omnipaque 350 and Hexabrix.

The present invention also provides for a kit for preparing an in situhydrogel polymer composition comprising: (a) a container with a firstamount of a diamine; (b) a container with a second amount of apolyglycidyl ether; and (c) optionally, a radiopaque material; andinstructions for combining the materials present in each of saidcontainers to produce the hydrogel polymer in situ in a mammal or in amedical device located in a mammal.

The present invention also sets forth a method of forming a hydrogelpolymer composition comprising the steps of: (1) forming a mixturecomprising a diamine and a polyglycidyl ether; (2) depositing saidmixture in a mammal or into a medical device located in a mammal; and(3) allowing said mixture to cure and form said hydrogel polymercomposition.

BRIEF DESCRIPTION OF THE DRAWINGS

Not Applicable.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

As used herein, the term “biocompatible” describes the characteristic ofa polymer or other material to not have a toxic or injurious effect(i.e., does not cause infection or trigger an immune attack, oradversely affect the biological function in the expected conditions ofuse) in a mammalian biologic system.

As used herein, the term “radiopaque” or “contrast agent” is used todescribe a material that is not transparent to X-rays or other forms ofradiation. Radiopaque materials include but are not limited to sodiumiodide, potassium iodide, barium sulfate, gold, tungsten, platinum,metrizamide, iopamidol, iohexol, iothalamate sodium, meglumine,Visipaque 320, Hypaque, Omnipaque 350, Hexabrix and tantalum powder).

As used herein, the term “embolization device” describes a substancethat is introduced into a space, a cavity, or lumen of a blood vessel orother like passageway that partially or totally fills the space orcavity or partially or totally plugs the lumen. For example, an emboliccomposition can be used for occlusion of a vessel leading to a tumor orfibroid, occlusion of a vascular malformation, such as an arteriovenousmalformation, occlusion of a left atrial appendage, as a filler for ananeurysm sac, as an endoleak sealant, as an arterial sealant, as apuncture sealant, or for occlusion of any other lumen such as, forexample, a fallopian tube.

As used herein, the term “lumen” or “luminal” refers to various holloworgans or vessels of the body such as veins, arteries, intestines,fallopian tubes, trachea and the like. Lumen is also used to refer tothe tubes present in a catheter system (i.e., “multi-lumen” catheter).

As used herein, the term “alkyl,” by itself or as part of anothersubstituent, means, unless otherwise stated, a straight or branchedchain, or cyclic hydrocarbon radical, or combination thereof, which canbe fully-saturated, mono- or polyunsaturated and can include di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Examples of saturatedhydrocarbon radicals include groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,(cyclohexyl)ethyl, cyclopropylmethyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds.

As used herein, the term “does not degrade” or “non-degradable” refersto the characteristic of a substance, such as a polymeric material, toresist being physically, chemically, or enzymatically decomposed(metabolized) into smaller molecular weight fragments, in aphysiological environment to a degree that it impacts the function orbiocompatibility of the material. Generally, a composition that does notdegrade in an in vivo environment is one that is stable in aqueous pH 10solution for at least 18 days which is equivalent to 10 years in vivo.The amount of degradation will typically be less than about 5% byweight, more preferably less than 4%, still more preferably less than2%, even more preferably less than 1%, and most preferably less thanabout 0.5% by weight, relative to the overall weight of the polymercomposition.

As used herein, the term “weight percent” refers to the mass of onecomponent used in the formulation of a polymer composition divided bythe total mass of the polymeric product and multiplied by 100%.

EMBODIMENTS OF THE INVENTION I. Compositions

In one aspect, the present invention provides hydrogel polymercompositions that are biocompatible, pose no embolic risk, arenon-degradable, and are stable in blood contact for >10 years. The gelcompositions of the present invention are suitable for a variety of invivo applications, including but not limited to, use in an intraluminalgraft, as a luminal embolization device, in an inflatable occlusionmember, and as a tissue bulking device, among others.

In its broadest concept, the hydrogel polymer compositions of thepresent invention are formed from at least two monomer components, i.e.,a diamine and a polyglycidyl ether. The resulting gel composition of theinvention does not contain a hydrolyzable group such as an ester groupor amide group, among others. As a result, the present compositionsexhibit increased stability in a physiological environment, and reducethe likelihood of breakdown in vivo.

Turning first to the diamine component of the present compositions, asuitable diamine monomer can be essentially any diamine compound inwhich each nitrogen atom is independently either an amino or analkylamino group, and is sterically free to react with an epoxide moietyon a polyglycidyl ether. Typically, the diamine monomer has a molecularweight of between about 100 to about 2500; and in certain embodimentsthe diarnine monomer is biocompatible. In one group of embodiments, thediamine is a polyoxyalkylene compound having amino or alkylaminotermini. In a preferred embodiment, the polyoxyalkylene compound hasamino termini. Suitable diamine monomers for the hydrogel polymercomposition include, but are not limited to, polyethylene glycol diamine(also referred to as PEG-diamine or O,O'-Bis(2-aminoethyl)polyethyleneglycol; CAS No. 24991-53-5), di-(3-aminopropyl) diethylene glycol (alsoreferred to as O,O'-Bis(3-aminopropyl)diethylene glycol, diethyleneglycol di-(3-aminopropyl)ether or3-{2-[2-(3-Amino-propoxy)-ethoxy]ethoxy}-propylamine; CAS No.4246-51-9), polyoxypropylenediamine (available from Huntsman PerformanceProducts, Texas, USA; CAS No. 9406-10-0), polyetherdiamine (availablefrom Huntsman Performance Products, Texas, USA; CAS No. 194673-87-5),polyoxyethylenediamine (available from Huntsman Performance Products,Texas, USA; CAS No. 65605-36-9), triethyleneglycol diamine (also knownas 3,6-dioxa-octamethylenediamine; CAS No. 929-59-9), and mixturesthereof. In one embodiment, the diamine compound is di-(3-aminopropyl)diethylene glycol (available from Aldrich Chemical Company, Wisconsin,USA). In another embodiment, the diamine is a mixture of polyethyleneglycol (400) diamine (available from Polypure Inc., Oslo, Norway; orfrom Tomah Inc., Wisconsin, USA) and di-(3-aminopropyl)diethyleneglycol. In yet another embodiment, the diamine a mixture ofpolyoxyethylenediamine and di-(3-aminopropyl)diethylene glycol. Othersuitable diamine monomers for the present composition will be apparentto those skilled in the art.

A second component for the gels of the present invention is apolyglycidyl ether. As used herein, the polyglycidyl ether monomer isany compound possessing at least two glycidyl ether functional groups,and preferably at least three glycidyl ether functional groups. In someembodiments, the polyglycidyl compound has at least two glycidyl ethergroups and a molecular weight between 100 and 2000. Polyglycidyl ethershaving two glycidyl ether groups are alternatively referred to in theart as diglycidyl ethers; while polyglycidyl ethers having threeglycidyl groups are referred to as triglycidyl ethers. In mostembodiments of the present invention, the polyglycidyl ether isbiocompatible. Suitable polyglycidyl ethers for use in the compositioninclude, but are not limited to, bis[4-(glycidyloxy)phenyl]methane (CASNo. 2095-03-6), 2,2-bis[4-(glycidyloxy)phenyl]propane (CAS No.1675-54-3), bisphenol A propoxylate diglycidyl ether (CAS No.106100-55-4), 1,4-butanediol diglycidyl ether (CAS No. 2425-79-8),1,3-butanediol diglycidyl ether (CAS No. 3332-48-7),1,4-cyclohexanedimethanol diglycidyl ether (CAS No. 14228-73-0),diethylene glycol diglycidyl ether (CAS No. 4206-61-5), ethylene glycoldiglycidyl ether (CAS No. 2224-15-9 and CAS No. 72207-80-8), glyceroldiglycidyl ether (CAS No. 27043-36-3), neopentyl glycol diglycidyl ether(CAS No. 17557-23-2), poly(dimethylsiloxane)-diglycidyl ether terminated(CAS No. 130167-23-6), polyethylene glycol diglycidyl ether (CAS No.26403-72-5), poly(propylene glycol) diglycidyl ether (CAS No.26142-30-3), resorcinol diglycidyl ether (CAS No. 101-90-6), sorbitolpolyglycidyl ether (CAS No. 68412-01-1), polyglycerol polyglycidylether, pentaerythritol polyglycidyl ether (CAS No. 3126-63-4),diglycerol polyglycidyl ether (CAS No. 68134-62-3), glycerolpolyglycidyl ether (CAS No. 25038-04-4), polyproylene glycol diglycidylether (CAS No. 26142-30-3), resorcinol diglycidyl ether (CAS No.101-90-6), glycidyl ester ether of p-hydroxy benzoic acid (CAS No.7042-93-5), neopentyl glycol diglycidyl ether (CAS No. 17557-23-2),1,6-hexanediol diglycidyl ether (CAS No. 16096-31-4), bisphenol A (PO)₂diglycidyl ether (available from Nagase ChemteX Corp., Osaka, Japan),o-phthalic acid diglycidyl ester (CAS No. 7195-45-4), hydroquinonediglycidyl ether (CAS No. 2425-01-6), bisphenol S diglycidyl ether (CASNo. 13410-58-7), terephthalic acid diglycidyl ester (CAS No. 7195-44-0),trimethylolpropane triglycidyl ether (CAS No. 30499-70-8), glycerolpropoxylate triglycidyl ether (CAS No. 37237-76-6), trimethylolethanetriglycidyl ether, triphenylolmethane triglycidyl ether (CAS No.106253-69-4),as well as mixtures thereof. Other polyglycidyl etherssuitable for use in the present invention will be apparent to oneskilled in the art.

In one embodiment, the polyglycidyl ether is a mixture oftrimethylolpropane triglycidyl ether and polyethylene glycol diglycidylether (both available from Aldrich Chemical Company, Wisconsin, USA). Inanother embodiment, the polyglycidyl ether is a mixture of polyethyleneglycol (600) diglycidyl ether (available from Polysciences, Inc.,Pennsylvania, USA) and trimethylolpropane triglycidyl ether. In yetanother embodiment, the polyglycidyl ether is a sorbitol polyglycidylether (available from Nagase ChemteX Corp., Osaka, Japan). In yetanother embodiment, the polyglycidyl ether is a mixture of sorbitolpolyglycidyl ether and polyglycerol glycidyl ether. In yet anotherembodiment, the polyglycidyl ether is a mixture of pentaerythritolpolyglycidyl ether and trimethylolpropane polyglycidyl ether. One ofskill in the art will appreciate that the properties of the resultantgel composition can be carefully controlled by varying the amount ofpolyglycidyl ether or combinations of polyglycidyl ethers to control theamount of cross-linking in the gel, the hydrophilic or hydrophobiccharacter of the gel, as well as the cure time and viscosity of thepre-cure combination.

Optionally, the hydrogel polymer comprises at least one radiopaquematerial.

Radiopaque materials suitable for the present invention include but arenot limited to sodium iodide, potassium iodide, barium sulfate, gold,tungsten, platinum, Visipaque 320, Hypaque, Omnipaque 350, Hexabrix,metrizamide, iopamidol, iohexol, iothalamate sodium, meglumine, gold andtantalum powder. In some instances, it is preferable to use a blend ofradiopaque material, as is in the case when it desired that the gelcomposition loses radiopacity over time. For instance, a blend of asoluble contrast agent such as an iodinated aqueous solution and aninsoluble contrast agent such as barium sulfate can serve this purpose.The soluble contrast agent will leach out of the composition resultingin a progressive decrease in radiopacity of the composition over time.

The utility of the inventive gel compositions for many in vivoapplications is attributed, in part, to the ease in which the mechanicalproperties of the pre- and post-cure gel composition can be modified, asnoted above, simply through the judicious selection of the diamine andpolyglycidyl ether components, and the curing conditions. For example,the cure rate is affected, in part, by the molecular weight of themonomer components used, and the concentration of the curing solution.In more detail, using a polyglycidyl ether having more glycidyl ethergroups per monomer unit will provide a faster cure rate; using a higherconcentration of monomer components in the pre-cure gel composition willprovide a faster cure rate; and having a higher pH composition willprovide a faster cure rate. Other methods of modifying the cure rate ofthe inventive composition will be readily apparent to a skilled artisan.

In another example, the firmness/hardness property of the final gelcomposition will be determined, in part, by the hydrophilic/hydrophobicbalance of the monomer components. A higher proportion of hydrophobicmonomers can provide a firmer gel composition. The firmness is alsoaffected by the molecular weight of the monomer (i.e., a lower molecularweight provide a firmer gel), and the length of the monomer backbone ofthe polyglycidyl ether component (i.e., shorter polyglycidyl etherbackbone provides a firmer gel). Other methods of modifying thehardness/firmness property of the final gel composition will be readilyapparent to a skilled artisan.

In one embodiment, the composition comprises a hydrophilic diamine and ahydrophilic polyglycidyl ether. In another embodiment, the compositioncomprises a hydrophilic diamine and a hydrophobic polyglycidyl ether. Inyet another embodiment, the composition comprises a hydrophobic diamineand a hydrophilic polyglycidyl ether.

The gel composition can optionally incorporate water or another aqueousfluid to result in increased volume (or swelling) of the final gelcomposition. The swelling of the final gel composition is inverselyrelated to the firmness of the final gel. Depending of the proposedapplication, it is desirable that the inventive gel swells less thanabout 30 percent. In certain applications, such as in a embolizationdevice, minimal swelling can be preferred.

The hydrogel polymer composition can optionally comprise variousadditives that can alter the mechanical or physical properties of thepre- or post-cure gel composition, e.g., to increase cure rate, toreduce viscosity, to introduce radiopacity. In one illustrative example,hydroxide can be added to the pre-cure gel mixture to catalyze rate offormation (cure rate) of the hydrogel polymer. In another illustrativeexample, fumed silica can be added to the pre-cure gel mixture to giveit a thixiotropic character desirable for certain embolizationapplications. Other comonomers and additives can be incorporated to thegel composition to alter the thermoresponsiveness, elasticity,adhesiveness and hydrophilicity of the final gel composition.

Optionally, the gel compositions of the present invention can be used todeliver drugs to the target site. The drugs can be mixed in or attachedto the gel composition using a variety of methods. Some exemplary drugsand methods for attaching the drugs to the embolic composition aredescribed in J. M. Harris, “Laboratory Synthesis of Polyethylene GlycolDerivatives, ” Journal of Macromolecular Science-Reviews inMacromolecular Chemistry, vol. C-25, No. 3, pp. 325-373, Jan. 1, 1985;J. M. Harris, Ed., “Biomedical and Biotechnical Applications ofPoly(Ethylene Glycol) Chemistry”, Plenum, New York, pp. 1-14, 1992;Greenwald et al., “Highly Water Soluble Taxol Derivatives:7-Polyethylene Glycol Carbamates and Carbonates:”, J. Org. Chem., vol.60, No. 2, pp. 331-336, 1995, Matsushima et al., “Modification of E.Coli Asparaginase with 2,4-Bis(O-MethoxypolyethyleneGlycol)-6-Chloro-S-Triazine (Activated PEG.sub.2); Disapperance ofBinding Ability Towards Anti-Serum and Retention of Enzymic Activity,”Chemistry Letters, pp. 773-776, 1980; and Nathan et al., “Copolymers ofLysine and Polyethylene Glycol: A New Family of Functionalized DrugCarriers,” Bioconjugate Chem. 4, 54-62 (1993), each of which areincorporated herein by reference in its entirety.

As previously stated, the selection of monomer components for the gelcomposition will depend largely on the desired physical properties ofthe pre-cure monomer mixture and the final gel material, which is inturn is dependent on its intended application in vivo. Specific uses forthe gels of the present invention (including preferred monomers andamounts of monomers) are provided below as select embodiments of theinvention.

Stent Graft or Intraluminal Graft:

The present gel compositions are useful in a polymeric stent-graft orintraluminal graft (e.g., as described in U.S. Pat. No. 6,395,019)located in a mammal for the purpose of inflating the channels and cuffsof the graft to conform to the morphology of the lumen, and to impartsufficient strength to the graft to resist to kinking. As used herein,the term “stent graft” interchangeably refers to inflatable intraluminalgrafts as well as inflatable intralurninal stent grafts. For applicationin a stent graft or intraluminal device, it is preferable that thepre-cure gel composition comprise monomer components that arehydrophilic and biocompatible so as to minimize the embolic risk andtoxicity that can result in the event of accidental release of themonomeric components in the bloodstream during addition of the pre-curecomposition into the stent graft. Should accidental release occur,normal blood flow would then rapidly disperse the monomeric componentsand their concentration would fall below the level required to form asolid. Preferably, the pre-cure gel composition is soluble for at least3 minutes in the bloodstream; more preferably for at least 5 minutes;even more preferably for at least 8 minutes or until just before cure.

In a stent graft application, it is less desirable for the gelcomposition to cure quickly as the pre-cure mixture should remain fluidin order to travel through a delivery tube into the stent graft. Afterthe addition of the gel composition to the stent-graft, it is preferablefor the graft to remain initially less rigid, so that the filled graftmaterial can adjust and conform to the morphology of the vessel or lumenspace. In one embodiment, the gel composition has a cure time from about5 minutes to about 20 minutes. In another embodiment, the cure time isfrom about 10 to about 17 minutes. As stated above, it is beneficial forthe pre-cure composition be a flowable solution that can be deliveredthrough a delivery tube (e.g., catheter, syringe). In one embodiment,the viscosity of the pre-cure mixture is between about 10 to about 500cp (centipoise). In another embodiment, the viscosity of the pre-curemixture is between about 20 to about 100 cp, more preferably about 30cp.

After curing, the gel composition maintains its biocompatibility and isstable in the event of contact with blood. The cured gel compositionprovides desirable mechanical properties such as, an elastic modulusbetween about 60 and about 500 psi, more preferably about 100 to about400 psi, even more preferably about 200 to about 300 psi. Still further,the gel compositions that are used in stent-graft will typically be lowswelling compositions and exhibit a volume change upon curing betweenabout 0 to about 30 percent. As can be appreciated the pre-cureproperties and post-cure properties of the gel composition describedabove are merely examples and should not limit the scope of the presentinvention.

The inventive gel composition in a stent graft typically show little orno volume change after curing. In one embodiment, the gel compositionswells or shrinks less than about 20 percent after curing and hydration.In another embodiment, the gel composition swells or shrinks less thanabout 10 percent after curing and hydration. In yet another embodiment,the gel composition swells or shrinks less than 5 percent after curingand hydration. Low volume change of the gel mixture after curing andhydration is important in a stent graft material application. Excessivevolume change of the hydrogel polymer after curing and hydration canadversely affect the strength of the graft material located inside thebody lumen, and possibly jeopardize the safety of the mammal.

The hydrogel polymer can be comprised of any diamine or mixture ofthereof; however, in one embodiment, the diamine or mixture thereof is ahydrophilic diamine. In another embodiment, the diamine monomer isselected from the group consisting of polyoxyethylenediamine,triethyleneglycol diamine, polyethylene glycol diamine,di-(3-aminopropyl)diethylene glycol, or a mixture thereof. It isdesirable that the polyglycidyl ether component is also hydrophilic. Inone embodiment, the polyglycidyl ether component is a mixture of adiglycidyl ether and a triglycidyl ether. In another embodiment thepolyglycidyl ether component is mixture of polyethylene glycoldiglycidyl ether and trimethylolpropane triglycidyl ether. In yetanother embodiment, the polyethylene glycol diglycidyl ether ispolyethylene glycol (600) diglycidyl ether. Furthermore, the hydrogelpolymer can comprise a radiopaque material. In one embodiment, theradiopaque material is sodium iodide.

In one embodiment, the diamine is present in an amount of between about4 to about 20 weight percent of the hydrogel polymer; and thepolyglycidyl ether is present in an amount of between about 15 to about60 weight percent of the hydrogel polymer. In another embodiment,diamine is present in an amount of between about 5 to about 15 weightpercent of said polymer; and the polyglycidyl ether is present in anamount of between about 25 to about 40 weight percent of the hydrogelpolymer.

In yet another embodiment, the diamine is di-(3-aminopropyl)diethyleneglycol; the polyglycidyl ether is a mixture of polyethylene glycoldiglycidyl ether and trimethylolpropane triglycidyl ether; and theradiopaque material is selected from the group consisting of sodiumiodide, potassium iodide, barium sulfate, Visipaque 320, Hypaque,Omnipaque 350 and Hexabrix.

Embolic Compositions

In addition to the stent graft embodiments above, the present gelcompositions can be constructed for use as an embolization device.Embolization devices block or obstruct flow through a body lumen.Numerous clinical applications exist for embolization of both vascularand nonvascular body lumens. The most prevalent uses for an embolizationdevice include, but are not limited to, the neurological treatment ofcerebral aneurysms, AVMs (arteriovenous malformations) and AVFs(arteriovenous fistula), and the peripheral treatment of uterinefibroids and hypervascular tumors. However, embolization devices arealso useful in a variety of vascular or non-vascular body lumens ororifices, such as the esophagus, genital-urinary lumens, bronchiallumens, gastrointestinal lumens, hepatic lumens, ducts, aneurysms,varices, septal defects, fistulae, fallopian tubes, among others.Moreover, it should be appreciated that the gel composition as anembolization device can be used in conjunction with other components,such as endovascular grafts, stents, inflatable implants, fibers, coils,and the like. Other applications of embolization devices are describedin co-pending U.S. patent application Ser. No. 11/031,311, titled“Methods, Materials, and Devices for Embolizing Body Lumens” to Whirleyet al., the disclosure of which is incorporated herein by reference inits entirety.

For application in an embolic composition, it is preferable that thepre-cure gel composition is biocompatible and exhibit controllablesolubility which is independent of the environment in which the emboliccomposition is delivered (e.g., in blood or other body fluid). Morespecifically, as the pre-cure gel mixture will be applied directly tothe site for occlusion, in one aspect, it is be desirable for thepre-cure composition to be less soluble in blood or other body fluid andto remain relatively localized at the site of administration. In otherembodiments, it is be desirable for the pre-cure gel composition todisperse through the vasculature as to provide a complete “cast” of asegment of the arterial tree after the gel composition cures (such asfor a hypervascular tumor or an AVM), thereby reducing the opportunityfor development of collateral perfusion. Typically, the present hydrogelpolymer in an embolic application has a viscosity of 100 cp or higher, acontrollable hydrophobicity and a faster cure rate than the compositionsdescribed above.

Applicants have found that for embolization applications it is desirableto increase the viscosity and hydrophobicity of the uncured material andthereby facilitate controlled placement without unintended embolizationof distal vascular beds. This can be accomplished by reducing oreliminating saline or water from the gel composition. Reducing thesaline and water prior to curing has been found to achieve the bestviscosity for delivery into the body lumen, maximizes the degradationresistance of the cured polymer and maximizes the cohesiveness andhydrophobicity of the gel material.

Low viscosity formulations of the gel composition can also be used todeeply penetrate tumor vascular beds or other target embolization sitesprior to curing of the composition. Occlusion balloons (such as aSwan-Ganz dual-lumen catheter or the EQUINOX™ Occlusion Balloon Cathetermanufactured by Micro Therapeutics, Inc. of Irvine, Calif.) or otherancillary flow-blocking devices, such as brushes or other obstructivedevices, some of which can be placed on a catheter or stent, such asthose sometimes placed across a cerebral aneurysm to be embolized, canbe used to prevent flow of the embolic composition beyond the targetembolization site.

High viscosity and/or thixotropic (shear-thinning) formulations of thesecompositions can be used to limit the flow to the neighborhood of thedelivery catheter and to facilitate the tendency of the gel compositionto remain in the vicinity of the location in which it was delivered,sometimes even in the presence of substantial blood flow or otherforces. Viscosity and/or thixotropy characteristics can be increased byadding bulking and/or thixotropic agents, such as fumed silica. Thebulking agent can be added anytime during the formation of the gelcomposition, but is typically preloaded with one of the components, andpreferably preloaded with the monomer/polymer or buffer solution.

Some examples of additives that are useful include, but are not limitedto, sorbitol or fumed silica that partially or fully hydrates to form athixotropic bulking agent, and the like. Desirable viscosities for thepre-cure gels range from about 5 centipoise (cP) for a low-viscosityformulation (such as might be used to deeply penetrate tissue in ahypervascular tumor) up to about 1000 cP or higher for a higherviscosity formulation (such as might be used to treat a sidewallcerebral aneurysm while minimizing the chance of flow disturbance to theembolic composition during the curing process). As can be appreciated,other embodiments of gels can have a higher or lower viscosity, and thegel composition is not limited to such viscosities as described above.

After curing, the embolic composition maintains its highbiocompatibility and is stable in blood. The cured embolic compositionprovides desirable mechanical properties such as, a specific gravitybetween 1.15 to over 1.4, an elastic modulus between about 30 and about500 psi, a strain to failure of about 25 percent to about 100 percent ormore, a volume change upon curing between about 0 percent to about 200percent or more, and a water content between less than 5 percent togreater than about 60 percent. In one embodiment, the volume change ofthe gel composition upon curing is less than about 20 percent. As can beappreciated the pre-cure properties and post-cure properties of the gelcomposition described above are merely examples and should not limit thescope of the embolic compositions of the present invention. The gelcomposition of the present invention can be modified to provide otherpre-cure and post-cure mechanical properties, as desired.

The hydrogel polymer can be comprised of any diamine or mixture ofthereof; however, in one embodiment, the diamine or mixture thereof is ahydrophilic diamine. In another embodiment, the diamine is a hydrophobicdiamine. The polyglycidyl ether can be hydrophilic or hydrophobic. Inone embodiment, in the gel composition, a hydrophilic diamine will bepaired with a less water-soluble, hydrophobic polyglyicdyl ether.Alternatively, in another embodiment, in the gel composition, a morewater-soluble hydrophilic polyglycidyl ether will be paired with a morehydrophobic diamine. The selection of suitable diamine and polyglycidylether components for the purpose of modify the mechanical properties ofthe pre-cure or the post-cure composition will be readily apparent to askilled artisan. For example, to increase the firmness of the final gelcomposition, a polyglycidyl ether, such as a triglycidyl ether, whichfunctions as a crosslinking agent, can be included in the composition. Askilled artisan will also recognize that the firmness of the formed gelcomposition will also be determined in part by the hydrophobic andhydrophilic balance of the monomer components, e.g., a higherhydrophobic percent provides a firmer hydrogel. In one embodiment, thediamine component is selected form the group consisting ofdi-(3-aminopropyl)diethylene glycol, polyoxyethylenediamine and, and amixture thereof. In another embodiment, the polyglycidyl ether isselected from the group consisting of sorbitol polyglycidyl ether,polyglycerol polyglycidyl ether, trimethylolpropane triglycidyl ether,and mixtures thereof. In another preferred embodiment, the gelcomposition includes a radiopaque agent.

In one embodiment, the diamine is present in an amount of between about7 to about 60 weight percent of the hydrogel polymer; and thepolyglycidyl ether is present in an amount of between about 7 to about55 weight percent of the hydrogel polymer. In another embodiment,diamine is present in an amount of between about 10 to about 45 weightpercent of said polymer; and the polyglycidyl ether is present in anamount of between about 14 to about 35 weight percent of the hydrogelpolymer.

In one embodiment, the diamine is present in an amount of between about5 to about 30 weight percent of the hydrogel polymer; and thepolyglycidyl ether is present in an amount of between about 40 to about90 weight percent of the hydrogel polymer. In another embodiment,diamine is present in an amount of between about 50 to about 75 weightpercent of said polymer; and the polyglycidyl ether is present in anamount of between about 10 to about 20 weight percent of the hydrogelpolymer.

In yet another embodiment, the diamine is di-(3-aminopropyl)diethyleneglycol; and the polyglycidyl ether is a mixture of pentaerythritolpolyglycidyl ether and trimethylolpropane polyglycidyl ether; and theradiopaque material is sodium iodide.

In yet another embodiment, the diamine is a mixture ofdi-(3-aminopropyl)diethylene glycol and polyoxyethylenediamine; thepolyglycidyl ether is sorbitol polyglycidyl ether; and the radiopaquematerial is selected from the group consisting of sodium iodide,potassium iodide, barium sulfate, Visipaque, Hypaque, Omnipaque, andHexabrix.

Tissue Bulking Device and Inflatable Occlusion Member:

The present gel compositions are useful for in vivo application in aninflatable occlusion member and as a tissue bulking device. The gelcomposition are useful in vivo in a number of tissue bulkingapplications (e.g., aiding functionality of various organs orstructures, such as assisting in closing a stricture (includingrestoring competence to sphincters to treat fecal or urinaryincontinence or to treat gastroesophageal reflux disease (GERD)),augmentation of soft tissue in plastic or reconstructive surgeryapplications (e.g., chin or cheek reshaping), replacing or augmentingherniated or degenerated intervertebral disks. The pre-cure compositioncan be directly contacted with the tissue material; or can be introducedinto an inflatable bag located in vivo. Alternatively, the pre-cure gelmixture can be added to an inflatable bag ex vivo, followed by placementof the bag inside the body.

It is preferable for the pre-cure gel composition to be biocompatibleand exhibit controllable solubility which is independent of theenvironment in which the pre-cure mixture is delivered (e.g., in bloodor other body fluid). More specifically, it is desirable for thepre-cure composition to be less soluble in blood or other body fluid andto remain relatively localized at the site of administration.Alternatively, in some embodiments, it is desirable for the pre-cure gelcomposition to diffuse to an in vivo site distal to the point ofadministration. Typically, the hydrogel polymer in a tissue bulkingapplication has a viscosity of 100 cp or higher and controllablehydrophobicity. The solubility of the pre- and post-cure composition ofthe invention can be modified by any means known to one skilled in theart (e.g., through the choice of the hydrophobic or hydrophilic monomercomponents).

Preferably, the gel composition will have a cure time that is longenough to allow the gel composition to fill and conform to the cavity towhich it is administered and/or long enough so that a medicalprofessional can sculpt or otherwise shape the composition prior to thecompletion of the gelling process. In one embodiment, the gelcomposition has a cure time of from about 10 seconds to about 30 minutesdepending on its intended site of administration. In another embodiment,the gel composition has a cure time of between about 30 seconds to about2 minutes.

After curing, the gel composition remains biocompatible and is stable inblood. The cured polymer provides desirable mechanical properties suchas, an elastic modulus between about 30 and about 500 psi, a strain tofailure of about 25 percent to about 100 percent or more, a volumechange upon curing between about 0 to about 30 percent or more, and awater content of about less than 60 percent. The volume change of thecured composition is preferably less than about 15 percent, and morepreferably less than about 10 percent. As can be appreciated thepre-cure properties and post-cure properties of the gel composition inan embolic application described above are merely examples and shouldnot limit the scope of the gel compositions of the invention. In oneembodiment, the gel time is between about 30 seconds to about 25minutes. In another embodiment, the gel time is between about 1 to about3 minutes.

The hydrogel polymer can be prepared from any diamine or mixture thereof(as described generally above). However, in one embodiment, the diamineor mixture thereof is a hydrophilic diamine. In another embodiment, thediamine is a hydrophobic diamine. Similarly, the polyglycidyl ether canbe hydrophilic or hydrophobic. In one embodiment, in the gelcomposition, a hydrophilic diamine will be paired with water-soluble,hydrophilic polyglyicdyl ether. In another embodiment, the diamine isdi-(3-aminopropyl)diethylene glycol. In another embodiment, thepolyglycidyl ether is sorbitol polyglycidyl ether. In yet anotherembodiment, the gel composition comprises a radiopaque agent. In yetanother embodiment, the radiopaque agent is Omnipaque, Visipaque, or acombination thereof. In yet another embodiment, the diamine isdi-(3-aminopropyl)diethylene glycol; the polyglycidyl ether is sorbitolpolyglycidyl ether; and the radiopaque material is a mixture ofVisipaque and Omnipaque.

In one embodiment, the diamine is present in an amount of between about4 to about 20 weight percent of the hydrogel polymer; and thepolyglycidyl ether is present in an amount of between about 15 to about60 weight percent of the hydrogel polymer. In another embodiment,diamine is present in an amount of between about 5 to about 15 weightpercent of said polymer; and the polyglycidyl ether is present in anamount of between about 25 to about 40 weight percent of the hydrogelpolymer.

Preparation of the Polymeric Hydrogels:

The gel composition can be made by combining the monomeric components inany order, as well as any additional monomers (comonomers) and otheradditives, under conditions suitable for formation of the polymer. Thereaction is carried out in a suitable solvent; that being any solventthat dissolves the monomer components. For example, water, alcohols,such as ethanol or methanol, also carboxylic amides, such asdimethylformamide, dimethylsufoxide, and also a mixture thereof, are allsolvents suitable for the reaction to make the hydrogel polymer. In oneembodiment, the reaction is carried out in a substantially aqueoussolution, e.g., in a basic sodium hydroxide solution (pH=7.4).Alternatively, the reaction can be carried out in under anhydrousconditions. Additionally, the skilled artisan will recognize that themechanical properties of the final hydrogel product can be modified bychanging at least the following variables: the choice of monomercomponents, the ratio of the monomer components (e.g. high or lowmolecular weight monomers), the concentration of the monomer(s), the pHof the reaction medium, the reaction time, and the rate of addition ofthe individual monomer components. For example, adding a triglycidylether in the composition, which can function as a crosslinking agent,can result in a gel material having increased hardness. Details areprovided in the examples below to guide one of skill in the art in thepreparation of the present gel compositions.

II. Method of Use

The hydrogel composition of the invention can be used in any medicalapplication, in which the presence of a non-degradable, biocompatiblehydrogel polymer is desired. More specifically, the present invention isparticularly suited for applications that benefit from the in situgelling characteristics. The present gel composition is especiallyuseful in an inflatable occlusion member, an intraluminal graft, atissue bulking device, and an embolization device.

In one aspect of the invention, the gel composition can be used in an invivo environment, for example, as an intraluminal graft, such as, in apolymeric stent graft, as described in U.S. Pat. No. 6,395,019, theentirety of which is incorporated herein by reference, to improve themechanical integrity of the stent graft. The '019 patent, describes thatmonomer components are added into the cuffs and channels of a stentgraft, which upon curing, the final gel composition imparts additionalstrength to and conforms to the stent graft sealing cuffs.

In another aspect of the invention, the gel composition is also beuseful as a tissue bulking (augmentation) device, such as, foraugmentation of dermal support within intradermal or subcutaneousregions for the dermis, for breast implants, or for sphincteraugmentation (i.e., for restoration of continence), among others. Inthis application, the pre-cure gel composition can be added to aninflatable bag located inside the body, or the pre-cure gel compositioncan be added to an inflatable bag ex vivo, which is then placed insidethe body.

In yet another aspect of the invention, the gel composition can beformed directly on the tissue surface in an in vivo environment. Medicalapplications in which direct contact of body tissue with the inventivematerial is beneficial include, but are not limited to, as a puncture orwound sealant, and as an embolization device.

In one aspect, the gel composition can be used as an embolization deviceto form a plug for a variety of biological lumens. The compositions canbe used to occlude blood vessels and other body lumens, such as,fallopian tubes and vas deferens, filling aneurysm sacs, and as arterialsealants. The embolization of blood vessels is useful for a number ofreasons; to reduce the blood flow and encourage atrophy of tumors suchas in the liver; to reduce blood flow and induce atrophy of uterinefibroids; for the treatment of vascular malformations, such as AVMs andAVFs; to seal endoleaks in aneurysm sacs; to stop uncontrolled bleeding;and to slow bleeding prior to surgery.

Method of Delivery:

The gel composition can be delivered to an in vivo site using anydelivery devices generally known to those skilled in the art. Theselection of the delivery device will depend on a number of factors,including the location of the in vivo site and whether a quick or slowcuring gel is desired. In most cases, a catheter or syringe is used. Insome cases, a multi- lumen catheter is used to deliver the hydrogelcomposition to the intended in vivo location, wherein the components ofthe composition are maintained in separate lumens until the time ofadministration. For example, a polyglycidyl ether component can bedelivered in the first lumen, while the diamine compound is deliveredthrough a second lumen. A third lumen can be used to deliver a contrastagent or other comonomers and/or additives to the in vivo site.

Alternatively, the components of the gel composition can be added to amulti-barrel syringe, wherein the barrels of the syringe are attached toa multi-pronged connector which is fitted to a spiral mixer nozzle(e.g., static mixer). As the components of the composition are pressedout of the syringe, they mix together in the nozzle and can be directlyapplied to tissue as needed in a relatively uniform, controlled manner.Additionally, the mixed components can be injected directly into tissueif the nozzle is further connected to a needle.

Injectable reaction mixture compositions also could be injectedpercutaneously by direct palpation, such as, for example, by placing aneedle inside the vas deferens and occluding the same with the injectedembolizing composition, thus rendering the patient infertile. Thecomposition can be injected with fluoroscopic, sonographic, computedtomography, magnetic resonance imaging or other type of radiologicguidance. This would allow for placement or injection of the in situformed hydrogel either by vascular access or percutaneous access tospecific organs or other tissue regions in the body.

The gel composition can be added to a stent-graft in an in vivoenvironment. For example, one method for inflating a stent graft in suchan environment is as follows: after the graft has been placed in thepatient's body, and it is time to inflate the graft, the monomercomponents which are contained in a sterile kit having separate syringesfor each monomer or mixtures thereof and also a timer, will bethoroughly mixed to begin the curing process. The contents are thentransferred to one of the syringes and that syringe is attached to anautoinjector which is connected to a tube that is in turn connected to abiopolymer delivery tube located on the proximal end of the catheter. Atthe appropriate time, the autoinjector is turned on and the contents ofthe syringe is moved through the tube in the catheter that is connectedon the distal end to a port on the graft where it enters the series ofcuffs and channels to inflate the graft material.

Additional methods of delivering the composition to an in vivo site arealso described in co-pending U.S. application Ser. No. 11/031,311

The following examples are meant to illustrate certain embodiments(e.g., stent graft fill, embolic composition, and tissue bulkingcompositions) of the invention and should not be construed in any way aslimiting the invention.

EXAMPLES Abbreviations Used:

PEGGE: Polyethylene glycol glycidyl etherTPTE: Trimethylolpropane triglycidyl etherDCA or DCA-221: Di-(3-aminopropyl)diethylene glycolcc: millilitersDI: deionized water1.5 N Gly-Gly: 1.5 N Glycine-glycine bufferEX-411: pentaerythritol polyglycidyl etherEX-321: trimethylpropane polyglycidyl ether (CAS No. 30499-70-8)

PBS: Phosphate Buffered Saline Example 1

The following table shows formulations (1-7) that are useful, in oneaspect of the invention, as stent graft fill material. Theseformulations can also find utility for other in vivo applications thatrequire a hydrogel polymer having the properties as shown in Table 1.

TABLE 1 Wt % % Weight of Mol # of % Wt Notes/ Formulation Material (g)Total Wt mmoles Gel Time Swelling Gain Observations 1 NaI (50%), 9.0059.0 20 cc, 4.00 10.50% 5.2 Hard material pH 7.40 min; 1 cc, PEGGE 2.2514.8 600 3.75 12 min TPTE 2.50 16.4 302 8.28 DCA221 1.50 9.8 222.00 6.762 NaI (50%), 9.00 57.1 20 cc, 4 min; 7 0.8 Hard material pH 7.40 1 cc,12 min PEGGE 2.25 14.3 600 3.75 TPTE 3.00 19.0 302 9.93 DCA221 1.50 9.5222.00 6.76 3 NaI (50%), 9.00 55.4 20 cc, 3.40 7 1.4 Hard material pH7.40 min; 1 cc, PEGGE 2.25 13.8 600 3.75 11.20 min Epoxy Aldrich 3.5021.5 302 11.59 DCA221 1.50 9.2 222.00 6.76 4 NaI (50%), 9.00 53.7 20 cc,3.40 5.6 0.4 Hard material pH 7.40 min; 1 cc, PEGGE 2.25 13.4 600 3.7511.20 min TPTE 4.00 23.9 302 13.25 DCA221 1.50 9.0 222.00 6.76 5 NaI(50%), 10.00 58.0 20 cc, 4.30 5.6 0 Hard material pH 7.40 min; 1 cc,PEGGE 2.25 13.0 600 3.75 11.40 min TPTE 3.50 20.3 302 11.59 DCA221 1.508.7 222.00 6.76 6 NaI (50%), 10.00 59.7 20 cc, 4.40 7 0 Hard material pH7.40 min; 1 cc, 12 PEGGE 2.25 13.4 600 3.75 min TPTE 3.00 17.9 302 9.93DCA221 1.50 9.0 222.00 6.76 7 NaI (50%), 10.00 55.6 20 cc, 4.30  1.20%−14% Hard material pH 7.40 min; 1 cc, PEGGE 2.25 12.5 600 3.75 11.40 minTPTE 3.50 19.4 302 11.59 DCA221 1.50 8.3 222.00 6.76 PBS 0.75 4.2

Example 2

The following table shows formulations (8-15) that are useful, in oneaspect of the invention, as a stern graft fill material. Theseformulations can also find utility for other in vivo applications thatrequire a hydrogel polymer having the properties as shown in Table 2.

TABLE 2 Weight Epoxy/ Gel Gel Observations/ Mol # of % amine Time Times% Notes, all with Formulation Material Weight Wt mmoles Total ratio 20cc 1 cc Swell 1 min mix 8 KI (100%) 9.0 56.3 4.58 8.30 13.45 18 Hard gelDCA 0.5 221.0 2.26 3.1 polyoxyethylene 3.0 2000.0 1.50 18.8 diamineSorbitol polyglycidyl 3.5 406.0 8.62 21.9 ether 9 KI (100%) 9.0 62.12.62 15.00 15.30 Soft gel DCA 0.5 221.0 2.26 3.4 polyoxyethylene 3.02000.0 1.50 20.7 diamine Sorbitol polyglycidyl 2.0 406.0 4.93 13.8 ether10 KI (100%) 9.0 62.1 5.72 11.00 14.00 5 soft gel DCA 0.5 221.0 2.26 3.4polyoxyethylene 1.5 2000.0 0.75 10.3 diamine Sorbitol polyglycidyl 3.5406.0 8.62 24.1 ether 11 KI (100%) 9.0 69.2 3.27 14.30 14.30 soft gelDCA 0.5 221.0 2.26 3.8 polyoxyethylene 1.5 2000.0 0.75 11.5 diamineSorbitol polyglycidyl 2.0 406.0 4.93 15.4 ether 12 KI (100%) 7.0 50.04.58 9.00 13.00 21 Hard gel DCA 0.5 221.0 2.26 3.6 polyoxyethylene 3.02000.0 1.50 21.4 diamine Sorbitol polyglycidyl 3.5 406.0 8.62 25.0 ether13 KI (100%) 7.0 56.0 2.62 12.30 14.00 soft gel DCA 0.5 221.0 2.26 4.0polyoxyethylene 3.0 2000.0 1.50 24.0 diamine Sorbitol polyglycidyl 2.0406.0 4.93 16.0 ether 14 KI (100%) 7.0 56.0 5.72 7.30 12.30 10 Hard gelDCA 0.5 221.0 2.26 4.0 Polyoxyethylene 1.5 2000.0 0.75 12.0 diamineSorbitol polyglycidyl 3.5 406.0 8.62 28.0 ether 15 KI (100%) 7.0 63.63.27 10.30 12.00 8 Hard gel DCA 0.5 221.0 2.26 4.5 polyoxyethylene 1.52000.0 0.75 13.6 diamine Sorbitol polyglycidyl 2.0 406.0 4.93 18.2 ether

Example 3

The following table shows formulations (16-24) that are useful, in oneaspect of the invention, stent graft fill material. These formulationscan also find utility for other in vivo applications that require ahydrogel polymer having the properties as shown in Table 3.

TABLE 3 Weight Epoxy/ Gel Gel Mol # of % amine Time Time % FormulationMaterial Weight Wt mmoles Total ratio 20 cc 1 cc Swell 16 Omnipaque 9.051.4 2.90 8.30 14:30    7.0% Buffer 1.5N pH 7.6 3.0 17.1 DCA221 1.5 2216.79 8.6 Sorbitol 4.0 406 9.85 22.9 polyglycidyl ether 17 Omnipaque 10.050.0 3.99 11.00 14:20 5.6-7.0% Buffer 1.5N pH 7.6 3.0 15.0 DCA221 1.5221 6.79 7.5 Sorbitol 5.5 406 13.55 27.5 polyglycidyl ether 18 Visipaque12.0 60.0 3.63 11.13 12.56   2.80% DCA 1.5 221.0 6.79 7.5 1.5N Gly-Gly1.5 7.5 Sorbitol 5.0 406.0 12.32 25.0 polyglycidyl ether 19 Visipaque11.0 59.5 2.90 13 14.3 DCA 1.5 221.0 6.79 8.1 1.5N Gly-Gly 2 10.8Sorbitol 4.0 406.0 9.85 21.6 polyglycidyl ether 20 Omnipaque 10.0 47.63.99 11.00 14:20 5.6-7.0% Buffer 1.5N pH 7.6 3.0 14.3 DI 1.0 4.8 DCA2211.5 221 6.79 7.1 Sorbitol 5.5 406 13.55 26.2 polyglycidyl ether 21Omnipaque 10.5 48.3 3.81 11.00 20.00 5.6-7.0% Buffer 1.5N pH 7.6 4.520.7 DCA221 1.5 221 6.79 6.9 Sorbitol 5.3 406 12.93 24.1 polyglycidylether 22 Visipaque 12.0 55.8 3.63 16 15.4 5.6-7.0% Di 1.0 4.7 DCA 1.5221.0 6.79 7.0 1.5N Gly-Gly 2 9.3 Sorbitol 5.0 406.0 12.32 23.3polyglycidyl ether 23 Visipaque 12.0 58.5 3.63 12.08 13.2 4% in DI 0.52.4 graft DCA 1.5 221.0 6.79 7.3 1.5N Gly-Gly 1.5 7.3 Sorbitol 5.0 406.012.32 24.4 polyglycidyl ether 24 Visipaque 11.4 55.6 3.63 11 14.3  6.00% Omnipaque 0.6 2.9 DCA 1.5 221.0 6.79 7.3 1.5N Gly-Gly 2 9.8Sorbitol 5.0 406.0 12.32 24.4 Polyglycidyl ether

Example 4

The following table shows formulations (EM1-EM12) that are useful, inone aspect of the invention, as embolic materials. These formulationscan also find utility for other in vivo applications that require ahydrogel polymer having the properties as shown in Table 4.

TABLE 4 # of Weight Reactive Weight Components (g) FW mmoles Sites % GelTime Comments EM-1  1 EX-411 3.00 411 7.30 4 60.0  7:10 syringe Somefloating material. EX-321 0.50 321 1.56 3 10.0 Soft, non-elastic, 2 NaI(100%) 1.00 20.0 fractionating slug. 3 DCA221 0.50 221 2.26 2 10.0 Total5.00 100.0 EM-2  1 EX-411 3.00 411 7.30 4 57.1  7:15 syringe Floatingmaterial. EX-321 0.25 321 0.78 3 4.8 Slightly firm slug 2 NaI (100%)1.00 19.0 3 DCA221 1.00 221 4.52 2 19.0 Total 5.25 100.0 EM-3  1 EX-4113.00 411 7.30 4 54.5 10:27 syringe Floating material. Soft, EX-321 1.00321 3.12 3 18.2 wet, non-elastic slug. 2 NaI (100%) 1.00 18.2 3 DCA2210.50 221 2.26 2 9.1 Total 5.50 100.0 EM-4  1 EX-41l 3.00 411 7.30 4 50.0 6:12 syringe Floating material. Very EX-321 1.00 321 3.12 3 16.7 hardslug. 2 NaI (100%) 1.00 16.7 3 DCA221 1.00 221 4.52 2 16.7 Total 6.00100.0 EM-5  1 EX-411 2.00 411 4.87 4 53.3  6:20 syringe Floatingmaterial. Soft, EX-321 0.25 321 0.78 3 6.7 elastic slug. 2 NaI (100%)1.00 26.7 3 DCA221 0.50 221 2.26 2 13.3 Total 3.75 100.0 EM-6  1 EX-4112.00 411 4.87 4 47.1 No cure time Floating material. EX-321 0.25 3210.78 3 5.9 collected. Material in PBS does not 2 NaI (100%) 1.00 23.5Extended, cure- demonstrate 3 DCA221 1.00 221 4.52 2 23.5 should havere- hydrophobicity. Slightly Total 4.25 100.0 mixed “grainy” texture.EM-7  1 EX-411 2.00 411 4.87 4 44.4  6:20 syringe Floating material.Soft, EX-321 1.00 321 3.12 3 22.2 non-elastic, fractionating 2 NaI(100%) 1.00 22.2 slug. 3 DCA22I 0.50 221 2.26 2 11.1 Total 4.50 100.0EM-8  1 EX-411 2.00 411 4.87 4 40.0  4:25 syringe Very small amountEX-321 1.00 321 3.12 3 20.0 At 4:00 drops floating material. Hot 2 NaI(100%) 1.00 20.0 became strings. exotherm, −75 C. Very 3 DCA221 1.00 2214.52 2 20.0 hard slug. Total 5.00 100.0 EM-9  1 EX-411 2.50 411 6.08 462.5  10:5 syringe Material in PBS cured at EX-321 0.20 321 0.62 3 5.08:00 2 NaI (100%) 1.00 25.0 3 DCA221 0.30 221 1.36 2 7.5 Total 4.00100.0 EM-10 1 EX-411 2.50 411 6.08 4 56.8  7:05 syringe Drops becamestrings at EX-321 0.40 321 1.25 3 9.1 2:45. Soft, fractionating 2 NaI(100%) 1.10 25.0 slug. 3 DCA221 0.40 221 1.81 2 9.1 Total 4.40 100.0EM-11 1 EX-41 1 3.00 411 7.30 4 47.6  5:36 syringe At 1:37, drops becameEX-321 1.00 321 3.12 3 15.9 Ice @ 37 C. strings. 5:50 material 2 NaI(100%) 1.70 27.0 cured at 7:36 cure in PBS. Soft elastic, 3 DCA221 0.60221 2.71 2 9.5 slug. Total 6.30 100.0 EM-12 1 EX-411 3.00 411 7.30 444.1  4:45 Syringe Material cure in PBS EX-321 1.50 321 4.67 3 22.1 1 cc@ 8:15 @ 5:47 2 NaI (100%) 1.70 25.0 Injected Ice in blood 3 DCA221 0.60221 2.71 2 8.8 6.80 100.0

Example 5

Formulation 7 was prepared according to the following experimentalprocedure.

The mixture of polyethylene glycol diglycidyl ether andtrimethylolpropane triglycidyl ether is added to a single syringe.Di-(3-aminopropyl)ether diethylene glycol is added to a second syringe.The two syringes are connected using a delivery tube and ping-pongedmixed between syringes for approximately 20 seconds, with the syringedemptied fully every time with each stroke (approximately 1stroke/second). A two milliliter sample stored in a 20 millilitersyringe cures in approximately 13 minutes at room temperature. Thiscorresponds to an in vivo cure time of 13 minutes in an inflatableendovascular graft.

1. An in situ formed hydrogel polymer, comprising: (a) a first amount ofa diamine; and (b) a second amount of a polyglycidyl ether; wherein eachof (a) and (b) are present in a mammal or in a medical device located ina mammal in an amount to produce an in situ formed hydrogel polymer thatis biocompatible; and has a cure time after mixing of from about 10seconds to about 30 minutes; and wherein the volume of said hydrogelpolymer swells less than 30 percent after curing and hydration.
 2. Thecomposition of claim 1, further comprising a radiopaque material.
 3. Thecomposition of claim 1, wherein said radiopaque material is selectedfrom the group consisting of sodium iodide, potassium iodide, bariumsulfate, Visipaque 320, Hypaque, Omnipaque 350 and Hexabrix.
 4. Thecomposition of claim 1, wherein said polyglycidyl ether is selected fromthe group consisting of trimethylolpropane triglycidyl ether, sorbitolpolyglycidyl ether, polyglycerol polyglycidyl ether, pentaerythritolpolyglycidyl ether, diglycerol polyglycidyl ether, glycerol polyglycidylether, trimethylolpropane polyglycidyl ether, polyethylene glycoldiglycidyl ether, resorcinol diglycidyl ether, glycidyl ester ether ofp-hydroxy benzoic acid, neopentyl glycol diglycidyl ether,1,6-hexanediol diglycidyl ether, bisphenol A (PO)₂ diglycidyl ether,hydroquinone diglycidyl ether, bisphenol S diglycidyl ether,terephthalic acid diglycidyl ester, and a mixture thereof.
 5. Thecomposition of claim 1, wherein said diamine is selected from the groupconsisting of (poly)alkylene glycol having amino or alkylamino terminiselected from the group consisting of polyethylene glycol (400) diamine,di-(3-aminopropyl) diethylene glycol r, polyoxypropylenediamine,polyetherdiamine, polyoxyethylenediamine, triethyleneglycol diamine, anda mixture thereof.
 6. The composition of claim 1, wherein said diamineis hydrophilic and said polyglycidyl ether is hydrophilic prior tocuring.
 7. The composition of claim 1, wherein said diamine ishydrophilic and said polyglycidyl ether is hydrophobic prior to curing.8. The composition of claim 1, wherein said diamine is hydrophobic andsaid polyglycidyl ether is hydrophilic prior to curing.
 9. Thecomposition of claim 1, wherein said in situ formed polymer is presentin a mammal or in a medical device located in the mammal in anintraluminal graft, as an embolization device, in an inflatableocclusion member, as a tissue bulking device.
 10. (canceled)
 11. Thecomposition of claim 9, wherein in said intraluminal graft, said polymeris comprised of: (a) di-(3-aminopropyl)diethylene glycol; and (b) amixture of polyethylene glycol glycidyl ether and trimethylolpropanetriglycidyl ether.
 12. (canceled)
 13. The composition of claim 9,wherein said embolization device is comprised of: (a) a mixture ofdi-(3-aminopropyl)diethylene glycol and polyoxyethylenediamine; and (b)sorbitol polyglycidyl ether.
 14. The composition of claim 9, whereinsaid embolization device is comprised of: (a)Di-(3-aminopropyl)diethylene glycol; and (b) a mixture ofpentaerythritol polyglycidyl ether and trimethylolpropane polyglycidylether.
 15. (canceled)
 16. The composition of claim 9, wherein in saidinflatable occlusion member or as a tissue bulking device, said polymeris comprised of: (a) di-(3-aminopropyl)diethylene glycol; and (b)sorbitol polyglycidyl ether.
 17. The composition of claim 2, whereinsaid diamine is present in an amount of between about 4 to about 20weight percent of said polymer; and said polyglycidyl ether is presentin an amount of between about 15 to about 60 weight percent of saidpolymer.
 18. The composition of claim 2, wherein said diamine is presentin an amount of between about 5 to about 15 weight percent of saidpolymer; and said polyglycidyl ether is present in an amount of betweenabout 25 to about 40 weight percent of said polymer. 19-20. (canceled)21. The composition of claim 2, wherein said diamine is present in anamount of between about 7 to about 60 weight percent of said polymer;said polyglycidyl ether is present in an amount of between about 7 toabout 55 weight percent of said polymer.
 22. The composition of claim 2,wherein said diamine is present in an amount of between about 10 toabout 45 weight percent of said polymer; said polyglycidyl ether ispresent in an amount of between about 14 to about 35 weight percent ofsaid polymer.
 23. The composition of claim 2, wherein said diamine ispresent in an amount of between about 5 to about 30 weight percent ofsaid polymer; said polyglycidyl ether is present in an amount of betweenabout 40 to about 90 weight percent of said polymer.
 24. (canceled) 25.A kit for preparing an in situ hydrogel polymer composition of claim 1comprising: (a) a container with a first amount of a diamine; (b) acontainer with a second amount of a polyglycidyl ether; (c) optionally,a radiopaque material; and instructions for combining the materialspresent in each of said containers to produce said hydrogel polymer insitu in a mammal or in a medical device located in a mammal.
 26. Amethod of forming a hydrogel polymer composition of claim 1, said methodcomprising: (1) forming a mixture comprising a diamine and apolyglycidyl ether; (2) depositing said mixture in a mammal or into amedical device located in a mammal; and (3) allowing said mixture tocure and form said hydrogel polymer composition.